Photoredox Fluoroalkylation of Hydrazones in Neutral and Reductive Modes

Article abstract of DOI:10.1002/adsc.202001381

Visible light promoted fluoroalkylation of hydrazones using 4-perfluoropyridine sulfides as fluoroalkyl radical sources is described. The process can proceed in neutral and reductive modes delivering either hydrazones or hydrazines, respectively, depending on structure of starting substrates and reaction conditions. For the reductive process, ascorbic acid is used as a terminal reductant, which recycles the photocatalyst and serves as a source of hydrogen towards nitrogen-centered radicals. (Figure presented.).

Full text of DOI:10.1002/adsc.202001381

Title: Photoredox Fluoroalkylation of Hydrazones in Neutral and
Reductive Modes
Authors: Boris van der Worp, Mikhail Kosobokov, Vitalij Levin, and
Alexander D. Dilman
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10.1002/adsc.202001381
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Photoredox Fluoroalkylation of Hydrazones in Neutral and
Reductive Modes
Boris A. van der Worp,a,b Mikhail D. Kosobokov,a Vitalij V. Levin,a Alexander D.
Dilmana*
a
N. D. Zelinsky Institute of Organic Chemistry, 119991 Moscow, Leninsky prosp. 47, Russian Federation
Fax: +7 499 135-53-28, E-mail: adil25@mail.ru
Lomonosov Moscow State University, Department of Chemistry, 119991 Moscow, Leninskie Gory 1-3, Russian
b
Federation
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
Abstract. Visible light promoted fluoroalkylation of
hydrazones using 4-perfluoropyridine sulfides as
fluoroalkyl radical sources is described. The process can
proceed in neutral and reductive modes delivering either
hydrazones or hydrazines, respectively, depending on
structure of starting substrates and reaction conditions. For
the reductive process, ascorbic acid is used as a terminal
reductant, which recycles the photocatalyst and serves as a
source of hydrogen towards nitrogen-centered radicals.
Keywords: fluorine; photocatalysis; hydrazones; radical
reactions; fluoroalkylation
Addition to carbon-nitrogen (azomethine) double
bonds is a fundamental transformation in organic
synthesis.[1,2] While the most widely used reactions of
azomethines are based on addition of nucleophiles,[1]
emerging radical approaches[2,3] provided an elegant
solution for a number of innate anionic chemistry
Figure 1. Commercial drugs containing hydrazone and
hydrazine motif.
problems e.g. substrate enolization and low C=N
bond electrophilicity. Among various azomethines,
hydrazones have one of the highest rates of radical
addition[2a] and therefore they became the most
attempt of perfluoroalkyl radical addition was
suitable substrates for this process.[3]
reported only in 2013 using Togni reagent,[9] which
Hydrazone and hydrazine scaffolds are common
was followed by a surge of papers[3b,c,10] (Scheme 1,
motifs in structures of a number of bioactive
path a). Transition metals such as copper,[10a-c]
compounds and even commercial top selling drugs[4]
silver[10d] and palladium[10e] in combination with
(Figure 1). Moreover, hydrazones are often used as
activated fluoroalkyl halides, Togni, Langlois or
valuable intermediates in organic synthesis,[5] such as
Ruppert-Prakash reagents were employed for the
equivalents of carbonyl compounds[6] or precursors of
generation of fluorinated radicals, though metal-free
heterocycles.[7] Therefore, radical processes involving
conditions were also reported.[10f]
hydrazones gained significant attention over the last
Since visible light photoredox catalysis can
decades.
provide very mild conditions for the radical
Due to unceasing demand of organofluorine
formation,[11] hydrazone fluoroalkylation using
compounds in pharmaceutical and agrochemical
iridium[12a,b] and gold[12c] metal complexes, as well as
industries,[8] addition of fluorinated radicals to
organic photocatalysts,[12d-f] was also documented.
hydrazones represents a transformation of great
Noteworthy, certain hydrazones were reported to
importance. While addition of alkyl radicals to
react with perfluoroalkyl iodides by direct
hydrazones was very well studied, first successful
photoinduced single electron transfer in the absence
1
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10.1002/adsc.202001381
Advanced Synthesis & Catalysis
acetate providing the highest yield of 3b. Use of 0.6
equiv of the zinc salt gave small decrease in the yield,
while other bases such as collidine and sodium
bicarbonate gave inferior results. Highly nucleophilic
DABCO led to degradation of starting sulfide,
presumably, owing to aromatic fluorine substitution
in the pyridine ring. The beneficial effect of zinc salts
for reactions of PyS-compounds may be ascribed to
its ability to tightly bind thiolate by-product.
With optimal conditions in hand, we evaluated the
applicability of the method to various types of
fluorinated groups and hydrazones (Scheme 2,
Overview). Thus, a range of PyfS-reagents 2a-d,
differing in a number of fluorines and serving as
sources of radicals CFnH3-n (n = from 3 to 0) was
prepared.
As
azomethines,
besides
N-
aminomorpholine hydrazone 1a, we also considered
conventional N-benzoylhydrazone 1c, as well as
amidrazone 1b, which has recently been introduced
by our group.[17] The addition of trifluoromethyl and
difluoromethyl radicals was quite effective for
morpholine derived hydrazone 1a and amidrazone 1b.
Addition of fluoromethyl radical to 1a did not
proceed, and only in case of 1b the expected product
was observed by 19F NMR (around 17% yield). Non-
fluorinated methyl radical was unreactive; however,
traces of methylated products were detected by GC-
MS analysis. As for benzoyl hydrazone 1c, it did not
give products with all set of radicals under standard
conditions.
Next, the method was tested with the scope of
more complex fluorinated radical precursors and
hydrazone acceptors (Scheme 2, Scope). Thus, gem-
difluorinated radicals (RCF2) generated from the
PyfS-reagents accessible from 1,1-difluoroalkenes[15a]
were found to be of reactivity similar to that of
difluoromethyl radical, significantly expanding the
area of the approach. Perfluorinated n-propyl radical
reacted smoothly furnishing product 3g. The reaction
is tolerant to electron-rich and electron-poor aromatic
rings both in hydrazone and radical counterparts with
product yields ranging from 53% to 91%. Pyridine
ring, which is amenable to Minisci-type radical
alkylations,[18] remained unaffected with the
corresponding product 3f obtained in 76% yield.
Isobutyraldehyde derived hydrazone gave the desired
product 3k in a decreased yield of 41%.
Further, we investigated the reactions of
hydrazones under reductive conditions. We focused
on a photocatalytic system involving ascorbic acid as
a stoichiometric reductant recently developed by our
group.[19] When combined with difluoromethyl
reagent 2b, N-benzoylhydrazone 1c was found to be
the most appropriate substrate leading to hydrazine
4a in excellent yield (Scheme 3, Optimization).
Besides ascorbic acid, various sources of hydrogen
such as Hantzsch ester, boron hydrides and silanes
were ineffective. Under the optimized reductive
conditions, we evaluated other sulfides 2a,c,d with
hydrazones 1a-c (Scheme 3, Overview). Thus,
Scheme 1. Radical reactions of hydrazones.
of any sensitizer.[13] In all these cases, radical
perfluoroalkylation of hydrazones generally leads to
formal
sp2-functionalization
product,
which
corresponds to electron neutral process (Scheme 1,
path a). To the best of our knowledge, no reductive
addition of fluorinated radicals to hydrazones leading
to hydrazines has been reported (path b). It is
noteworthy that visible light induced reductive
addition of non-fluorinated radicals derived from
redox-active esters[14a] or bis(catecholato)silicates[14b,c]
to C=N double bond was extensively studied. In those
approaches, Hantzsch ester or DIPEA were applied as
hydrogen atom donors.
Recently, we introduced reagents bearing 4-
tetrafluoropyridinylthio group as precursors of
radicals under photoredox conditions, and they were
coupled with silyl enol ethers, nitrones and
alkenes.[15] In this work we present our findings on
their reactions with most common types of
hydrazones. We demonstrate that by choice of
conditions, the process may be directed to either
neutral or reductive pathway.
Hydrazone 1a derived from 4-chlorobenzaldehyde
and N-aminomorpholine and difluoromethyl sulfide
2b, which can be readily obtained starting from
pentafluoropyridine,[15a] were selected as model
substrates, and their reaction was evaluated under
blue LED irradiation (Scheme 2, Optimization). The
reaction was best performed in the presence of fac-
Ir(ppy)3 (0.25% mol) as photocatalyst leading to
product 3b corresponding to the neutral mode of
addition. The reaction did not proceed without light,
but, surprisingly, noticeable yield 45% of 3b was
observed in the absence of photocatalyst. For 3h,
single X-ray structure was determined.[16]
Variation of solvents revealed that polar aprotic
solvents are preferable for the reaction, with dimethyl
sulfoxide affording the best results. Addition of water
(10 equiv) did not shut down the reaction, though led
to a reduced yield (54%). Base is important for
scavenging the produced acid with 1 equiv of zinc
hydrazones
1a,b
effectively
reacted
with
trifluoromethyl and difluoromethyl radicals, but
2
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10.1002/adsc.202001381
Advanced Synthesis & Catalysis
[a]
[b]
[c]
19F NMR yields using PhCF3 as internal standard.
Isolated yield.
Abbreviations: dtbbpy, 4,4'-di-tert-butyl-2,2'-
bipyridine; ppy, 2-phenylpyridinato-C2; 4-CzIPN, 2,4,5,6- tetra(9H-carbazol-9-yl)isophthalonitrile; POX, 3,7-dibiphenyl-
4-yl-10-(1-naphthyl)-10H-phenoxazine; 3DPA2FBN, 2,4,6-tris(diphenylamino)-3,5-difluorobenzonitrile.
[d]
Isolated as a
mixture of two C=N isomers (see SI for details).
Scheme 2. Fluoroalkylation of hydrazones under redox neutral conditions.
mixtures of products originating from neutral and
reductive pathways were formed. Fluoromethyl and
methyl sulfides 2c,d reacted poorly with hydrazones
of all types.
Since combination 1c/2b was most effective, a
series of N-benzoyl hydrazones were coupled with
sulfide 2b, as well as with other difluorinated PyS-
reagents[15] (Scheme 3, Scope). The reaction
proceeded with excellent yields with substrates
containing halogenated or electron-withdrawing
groups. In the presence of donor substituents,
considerable amounts of by-products originating from
radical attack on the aromatic ring were observed
(by-product 4gx was isolated and characterized).
Though, product 4g can still be isolated in moderate
yield. Fortunately, pyridine and even N-acetyl indole
fragments were tolerated (products 4h,i). Hydrazone
derived from hydrocinnamic aldehyde furnished good
yield (product 4j), but sterically hindered aliphatic
hydrazones gave noticeably decreased yields
(products 4k,l). In contrast to difluoroalkylations,
trifluoromethylation proceeded poorly presumably
due to radical addition on aromatics (product 4d, see
SI for analysis of by-products).
A
unified mechanism of the reactions of
hydrazones is shown in Scheme 4. The process starts
from single electron reduction of the sulfide by
photoexcited iridium complex generating the
fluorinated radical. It is believed that zinc acetate
facilitates cleavage of the PyfS-reagents either by
3
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10.1002/adsc.202001381
Advanced Synthesis & Catalysis
[a] 19F NMR yields using PhCF3 as internal standard. [b] Isolated yield. [c] Ratio of hydrazine/hydrazone.
Scheme 3. Fluoroalkylation of hydrazones under reductive conditions.
coordinating the starting substrate or by scavenging
PyfS-anion. Subsequent radical addition at the C=N
bond provides nitrogen-centered radical, which
reactivity depends on structural features and reaction
conditions. For morpholine substituted hydrazones, as
well as for amidrazones, oxidation by Ir(IV) is
possible and is followed by a loss of proton. On the
other hand, for N-benzoyl hydrazones, the oxidation
is problematic, but instead the hydrogen atom transfer
can be realized in the presence of ascorbic acid.[20] In
the latter case, ascorbate can also serve as single
electron reductant to convert Ir(IV) into Ir(III). Low
quantum yield for redox neutral reaction (0.04)
makes alternative chain mechanism less favorable.
To support our mechanistic hypothesis, we
conducted the model redox neutral reaction in the
presence of common radical traps (Scheme 5). Thus,
TEMPO completely inhibited the reaction, and the
trapping
product
A
was
detected.
1,1-
Scheme 4. Proposed mechanism.
Diphenylethylene also impeded the process giving
radical addition product B. Surprisingly, the presence
4
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10.1002/adsc.202001381
Advanced Synthesis & Catalysis
Experimental Section
of 2,6-di-tert-butyl-4-methylphenol (BHT) had
almost no effect on the reaction.
Reactions under redox neutral conditions; synthesis of
compounds 3 (general procedure 1).
A tube equipped with a stirring bar was evacuated,
backfilled with argon and successively charged with
hydrazone 1 (0.5 mmol), sulfide 2 (0.75 mmol), anhydrous
Zn(OAc)2 (92 mg, 0.5 mmol) and fac-Ir(ppy)3 (0.8 mg,
1.25 µmol), and DMSO (1 mL). The tube was evacuated,
refilled with argon, and closed with a screw cap. The
reaction vessel was irradiated with blue light (60 W/455
nm LED) for 15 h; during irradiation the mixture was
cooled with room temperature water. For the work-up, the
mixture was treated with a saturated aqueous solution of
K2CO3 (1 mL), diluted with water (3 mL) and extracted
with ethyl acetate (4×2 mL). The combined organic phases
were filtered through Na2SO4, concentrated under vacuum,
and the residue was purified by column chromatography
on silica gel.
[a]
19F NMR yield using PhCF3 as internal standard.
[b] Abbreviations: TEMPO, (2,2,6,6-tetramethylpiperidin-
1-yl)oxyl; BHT, 2,6-di-tert-butyl-4-methylphenol.
Reactions under reductive conditions; synthesis of
compounds 4 (general procedure 2).
Scheme 5. Mechanistic experiments.
A tube equipped with a stirring bar was evacuated,
backfilled with argon and successively charged with
hydrazone 1 (0.5 mmol), sulfide 2 (0.75 mmol), freshly
dried KOAc (73.6 mg, 0.75 mmol), anhydrous Zn(OAc)2
(92 mg, 0.5 mmol), ascorbic acid (132.1 mg, 0.75 mmol)
and fac-Ir(ppy)3 (0.8 mg, 1.25 µmol), and DMSO (1 mL)
The tube was evacuated, refilled with argon, and closed
with a screw cap. The reaction vessel was irradiated with
blue light (60 W/455 nm LED) for 4 h; during irradiation
the mixture was cooled with room temperature water. For
the workup, the mixture was diluted with water (5 mL) and
extracted with ethyl acetate (4×2 mL). The combined
organic phase was dried over Na2SO4, concentrated under
vacuum, and the residue was purified by column
chromatography on silica gel.
To demonstrate synthetic utility of our method, 10
mmol scale reactions were conducted using the same
power of light source (60W). The reductive
alkylation was suitable for scale-up affording 74%
yield of product 4a after 42 h of irradiation. At the
same time, for the synthesis of 3b (neutral conditions),
the reaction proceeded very slowly delivering full
conversion after 144 h of irradiation with the yield of
3b being only 20%. Also, a conversion of aldehydes
to difluorinated ketones was performed (Scheme 6).
Thus,
hydrazones
generated
using
N-
aminomorpholine were difluoroalkylated under
standard conditions followed by an acidic hydrolysis
of the hydrazone fragment. Though the overall yields
of ketones 5a,b were moderate, the reactions were
performed in a one-pot fashion without isolation of
intermediate products.
One-pot difluoroalkylation of aldehydes (general
procedure 3).
A tube equipped with a stirring bar was charged with
DMSO (1 mL), and then evacuated and backfilled with
argon. Aldehyde (0.5 mmol) and N-aminomopholine (53
mg, 525 mmol) were successively added and the mixture
was stirred for 1 hour at 25 °C. Anhydrous Zn(OAc)2 (92
mg, 0.5 mmol) and fac-Ir(ppy)3 (0.8 mg, 1.25 µmol) were
added into the reaction tube. The reaction vessel was
irradiated with blue light (60 W/455 nm LED) for 15 h;
during irradiation the mixture was cooled with room
temperature water. The mixture was diluted with 2M HCl
(1 mL) and stirred for additional 2 h at 50 °C. After the
completion of hydrazone hydrolysis (monitored by GC-
MS), the reaction mixture was extracted with diethyl ether
(4×2 mL). The combined organic phases were filtered
through Na2SO4, concentrated under vacuum, and the
residue was purified by column chromatography on silica
gel.
Scheme 6. Conversion of aldehydes to difluorinated
ketones.
Acknowledgements
In summary,
a
visible light promoted
This work was supported by the Russian Foundation for Basic
Research (project 19-03-00231).
fluoroalkylation of hydrazones was developed. Easily
accessible 4-perfluoropyridine sulfides were used as
convenient sources of difluorinated radicals. The
method enables fluoroalkylation in both neutral and
reductive modes providing fluorinated hydrazones or
hydrazines, respectively.
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6
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Advanced Synthesis & Catalysis
UPDATE
Photoredox Fluoroalkylation of Hydrazones in
Neutral and Reductive Modes
Adv. Synth. Catal. Year, Volume, Page – Page
Boris A. van der Worp, Mikhail D. Kosobokov,
Vitalij V. Levin, Alexander D. Dilman*
7
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